TITLE:

ANTIBODIES TO SPHINGOSINE-1-PHOSPHATE IN THE TREATMENT OF MURINE MODELS OF HUMAN CANCER (No. 66)

DATE:

Friday, February 18th, 2005

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

Roger Sabbadini, Department of Biology, San Diego State University

ABSTRACT:

The identification of signaling components that promote tumor growth is a critical step toward discovering therapeutic interventions for reducing cancer progression. Recent research has demonstrated that sphingosine kinase is a validated oncogene that produces the extracellular sphingolipid signaling molecule, sphingosine-1-phospate (S1P). S1P plays a pivotal role in cancer progression by regulating tumor proliferation, invasion and angiogenesis. We have developed a bio-specific monoclonal anti-S1P antibody (anti-S1P mAb) that could be used as a therapeutic molecular sponge to selectively neutralize the tumor promoter S1P. In this study the therapeutic potential of the anti-S1P mAb was analyzed both in vitro and in vivo. In vitro, the tumorigenic effect of anti-S1P mAb was evaluated in multiple cell lines representing a spectrum of histological subtypes. We demonstrated that S1P stimulates proliferation, promotes cell invasion and protects tumor cells from apoptosis induced by chemotherapeutic drugs and that all of these effects were neutralized by the anti-S1P mAb. We also demonstrate the ability of our antibody to inhibit angiogenesis. The anti-S1P mAb blocked both the migration of endothelial cells and their ability to form de novo capillary-like structures that resemble blood vessels using in vitro Matrigel models. In vivo, we investigated the ability of the anti-S1P mAb to reduce tumor volume and inhibit angiogenesis in multiple murine models. In several murine xenograft models the anti-S1P mAb alone as well in combination with the chemotherapeutic agent, paclitaxel, significantly reduced tumor progression. Using an in vivo Matrigel plug model we also demonstrated the anti-S1P mAb�s ability to block in vivo blood vessel formation induced by the angiogenetic factors VEGF and b-FGF. Further, in an orthotopic B16-F10 melanoma xenograft model was used to demonstrate that the mAb could arrest tumor progress by inhibiting angiogenesis alone. Taken together this study not only establishes S1P as a pleiotropic tumor promoter but suggests that the anti-S1P mAb may be clinically useful in reducing cancer progression by neutralizing the proliferative, invasive and angiogenetic effects of S1P. The success of the molecular absorption of S1P may represent a novel and innovative approach to the treatment of cancer.

HOST:

Jose Castillo

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